阅读说明：本技术 一种HIF-2α抑制剂PT2385的制备方法 (Preparation method of HIF-2 alpha inhibitor PT2385 ) 是由 邢峻豪 江玉琳 窦晓巍 张男侠 于 2021-08-27 设计创作，主要内容包括：本发明涉及一种HIF-2α抑制剂PT2385的制备方法。该方法以对二氟苯为原料,与3-氯丙酰氯发生傅克反应,生成中间体II,其与甲硫醇钠发生取代反应,生成中间体III,随后经氧化、还原及两步取代反应得到中间体VII,该中间体经氧化反应得到中间体VIII,其与正丁胺反应得到化合物IX,其经氟化反应和水解后,得到中间体X,最后经不对称还原反应得到终产品PT2385。与现有合成方法相比,本发明提供的工艺路线具有明显优势：原料廉价易得,操作简便,反应步数少,总收率高达47.6％,避免多步高温反应,易于工业化生产。。(The invention relates to a preparation method of a HIF-2 alpha inhibitor PT 2385. The method comprises the steps of taking difluorobenzene as a raw material, carrying out Friedel-crafts reaction on difluorobenzene and 3-chloropropionyl chloride to generate an intermediate II, carrying out substitution reaction on the intermediate II and sodium methyl mercaptide to generate an intermediate III, carrying out oxidation, reduction and two-step substitution reaction to obtain an intermediate VII, carrying out oxidation reaction on the intermediate to obtain an intermediate VIII, carrying out reaction on the intermediate VIII and n-butylamine to obtain a compound IX, carrying out fluorination reaction and hydrolysis to obtain an intermediate X, and finally carrying out asymmetric reduction reaction to obtain a final product PT 2385. Compared with the existing synthesis method, the process route provided by the invention has obvious advantages: the raw materials are cheap and easy to obtain, the operation is simple and convenient, the reaction steps are few, the total yield reaches 47.6 percent, multi-step high-temperature reaction is avoided, and the industrial production is easy to realize.)

1. A preparation method of a HIF-2 alpha inhibitor PT2385 is characterized by adopting the following technical scheme:

the method comprises the following operation steps:

s1: synthesis of intermediate II

Adding a compound I, 3-chloropropionyl chloride and anhydrous aluminum trichloride into a reaction bottle, then stirring for reaction, after the reaction is finished, adding water and ethyl acetate into the reaction bottle, performing liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing a solvent under reduced pressure to obtain an intermediate II;

s2: synthesis of intermediate III

Dissolving the intermediate II in an organic solvent, dropwise adding a sodium methyl mercaptide aqueous solution with the mass fraction of 20%, reacting at 25 ℃, detecting by TLC until the compound II disappears, adding water and ethyl acetate into the reaction liquid, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and removing the solvent under reduced pressure to obtain an intermediate III;

s3: synthesis of intermediate IV

Dissolving the intermediate III in dichloromethane, adding 85% m-chloroperoxybenzoic acid by mass fraction at 0 ℃, then stirring and reacting at 25 ℃, detecting by TLC until the compound III disappears, adding water into the reaction liquid, separating and extracting, drying the organic layer by using anhydrous sodium sulfate, carrying out suction filtration, decompressing and removing the solvent, and recrystallizing by using petroleum ether, ethyl acetate 4:1(v: v), mixed solvent to obtain an intermediate IV;

s4: synthesis of intermediate V

Dissolving the intermediate IV in methanol, adding sodium borohydride at 0 ℃, then stirring at 25 ℃ for reaction, detecting by TLC until the intermediate IV disappears, removing the solvent under reduced pressure, adding dichloromethane and water, performing liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain an intermediate V;

s5: synthesis of intermediate VI

Dissolving the intermediate V and 3-hydroxy-5-bromoxynil in N-methylpyrrolidone, adding a proper alkali, then reacting at 120 ℃, detecting by TLC until the intermediate V disappears, adding water into the reaction liquid, continuing stirring, carrying out suction filtration, and washing the filter cake with water to obtain an intermediate VI;

s6: synthesis of intermediate VII

Adding the intermediate VI, zinc cyanide and N, N-dimethylformamide into a reaction bottle, adding a1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane compound under the protection of nitrogen, reacting at 110 ℃, detecting by TLC until the intermediate VI disappears, adding water into the reaction solution, continuing stirring, carrying out suction filtration, and washing the filter cake with water to obtain an intermediate VII;

s7: synthesis of intermediate VIII

Dissolving the intermediate VII in dichloromethane, adding Dess-Martin oxidant in an ice bath, reacting at 25 ℃, detecting by TLC until the intermediate VII disappears, performing suction filtration, washing the filtrate with saturated sodium bicarbonate water solution and water in sequence, drying the organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain an intermediate VIII;

s8: synthesis of intermediate IX

Sequentially adding the intermediate VIII, cyclohexane, n-butylamine and trifluoroacetic acid into a reaction bottle, then reacting at 80 ℃, detecting by TLC until the intermediate VIII disappears, removing the cyclohexane under reduced pressure, adding ethyl acetate and water, carrying out liquid separation extraction, washing an organic layer by using a saturated sodium bicarbonate aqueous solution and a saturated salt solution in sequence, drying the organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and removing a solvent under reduced pressure to obtain an intermediate IX;

s9: synthesis of intermediate X

Adding the intermediate IX, anhydrous sodium sulfate and acetonitrile into a reaction bottle, then adding 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor), carrying out reflux reaction, detecting by TLC until the intermediate IX disappears, returning the temperature to room temperature, adding concentrated hydrochloric acid, continuing stirring for reaction for 0.5h, adding ethyl acetate and water, carrying out liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and removing the solvent under reduced pressure to obtain an intermediate X;

s10: synthesis of PT2385

Adding the intermediate X, triethylamine and formic acid into a reaction bottle, adding N- [ (1R,2R) -1, 2-diphenyl-2- (2- (4-methylbenzyloxy) ethylamino) ethyl ] -4-methylbenzenesulfonamide (chloro) ruthenium (II) under the protection of nitrogen, reacting at 25 ℃, detecting by TLC until the intermediate X disappears, adding ethyl acetate and water, performing liquid separation and extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, removing the solvent under reduced pressure to obtain a crude PT2385 product, and recrystallizing by using ethyl acetate to obtain a fine product.

2. The synthesis method of PT2385 as described in claim 1, wherein in the synthesis of intermediate II in step S1, the molar ratio of compound I, 3-chloropropionyl chloride and anhydrous aluminum trichloride is 1.0:1.0: 2.0-1.0: 1.0:5.0, and the reaction temperature is 100-150 ℃; in the synthesis of the intermediate III, the molar ratio of the intermediate II to the sodium methyl mercaptide is 1.0: 1.0-1.0: 3.0, and the organic solvent is one or more of acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide and N-methylpyrrolidone.

3. The method for synthesizing PT2385 as claimed in claim 1, wherein in the synthesis of intermediate IV in step S3, the molar ratio of intermediate III to m-chloroperoxybenzoic acid is 1.0: 2.0-1.0: 5.0.

4. The synthesis method of PT2385 as claimed in claim 1, wherein in the synthesis of intermediate V in step S4, the molar ratio of intermediate IV to sodium borohydride is 1.0: 1.0-1.0: 3.0.

5. A synthesis method of PT2385 as described in claim 1, wherein in the synthesis of intermediate VI in step S5, the base is one or more of sodium carbonate, potassium carbonate, cesium carbonate or potassium phosphate, preferably cesium carbonate, and the molar ratio of intermediate V, 3-hydroxy-5-bromoxynil and the base is 1.0:1.0: 1.0-1.0: 3.0: 4.0.

6. A synthesis method of PT2385 as described in claim 1, wherein in the synthesis of intermediate VII in step S6, the molar ratio of intermediate VI, zinc cyanide and 1,1 "-bis (diphenylphosphino) ferrocene dichloropalladium (II) dichloromethane complex is 1.0:1.0:0.01 to 1.0:2.0: 0.05.

7. The synthesis method of PT2385 as claimed in claim 1, wherein in the synthesis of intermediate VIII in step S7, the molar ratio of intermediate VII to Dess-Martin oxidant is 1.0: 1.0-1.0: 5.0.

8. The method for synthesizing PT2385 as claimed in claim 1, wherein in the synthesis of intermediate IX in step S8, the molar ratio of intermediate VIII, n-butylamine and trifluoroacetic acid is 1.0:1.0: 0.1-1.0: 2.0: 0.3.

9. The method for synthesizing PT2385 as claimed in claim 1, wherein in the synthesis of intermediate X in step S9, the molar ratio of intermediate IX, anhydrous sodium sulfate, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt and concentrated hydrochloric acid is 1.0:2.0:2.0: 10.0-1.0: 6.0:6.0: 20.0.

10. A synthesis method of PT2385 as described in claim 1, wherein in the synthesis of PT2385, the molar ratio of intermediate X, triethylamine, formic acid and N- [ (1R,2R) -1, 2-diphenyl-2- (2- (4-methylbenzyloxy) ethylamino) ethyl ] -4-methylbenzenesulfonamide (chloro) ruthenium (II) is 1.0:2.0:3.0: 0.001-1.0: 4.0:10: 0.005.

Technical Field

The invention relates to the technical field of medicine manufacturing, in particular to a novel method for preparing HIF-2 alpha inhibitor PT 2385.

Background

The HIF transcription complex is the key factor for sensing oxygen concentration change, and the HIF is composed of two different DNA binding proteins, namely HIF alpha and HIF beta, wherein the HIF alpha comprises HIF-1 alpha, HIF-2 alpha and HIF-3 alpha, and the HIF beta comprises HIF-1 beta, HIF-2 beta and HIF-3 beta. Under normal conditions, HIF alpha is modified by hydroxylation under the action of Prolyl Hydroxylase (PHD), and the modified HIF alpha is degraded by ubiquitination, so that the HIF alpha in cells maintains low expression level. Under hypoxic conditions, HIF α is protected from degradation, binding to HIF β and specific DNA sequences (HRE) in hypoxia regulated genes to activate expression of downstream genes. Studies have shown that dysfunction of HIF-2 α is a key factor in the drive of cancers such as renal clear cell carcinoma. A common feature of these related cancers is the excessive accumulation of HIF-2. alpha. protein. As a transcription factor, HIF-2 α has long been considered non-targetable because most transcription factors lack a cavity for binding to small molecule inhibitors. Researchers at the southwestern medical center, texas, usa have discovered a binding compartment in HIF-2 α that is critical for achieving functional heterodimeric assembly of HIF-2 α and HIF-1 β, and that this protein interaction may be blocked by small molecule inhibitors.

Based on the above findings, the HIF-2 α allosteric inhibitor was developed by Peloton Therapeutics in the united states, with PT2385 in phase II clinical trials. The synthesis of PT2385 (as shown in Scheme 1) is reported in WO2015035223a1 and document j.med.chem.2018,61,9691-. The method comprises the steps of taking para-fluorophenol as a raw material, reacting with 3-chloropropionyl chloride to obtain an intermediate B, carrying out rearrangement and Friedel-crafts reaction to obtain an intermediate C, reacting the intermediate C with dimethylaminothioformyl chloride to obtain an intermediate D, carrying out heating rearrangement to obtain an intermediate E, carrying out hydrolysis reaction to obtain an intermediate F, reacting the intermediate F with methyl iodide to obtain an intermediate G, carrying out oxidation reaction on the intermediate G to obtain an intermediate H, reacting the intermediate H with 1, 2-bis (trimethylsiloxy) ethane to obtain a ketal product intermediate I, carrying out two-step substitution reaction and deprotection on the intermediate I to obtain an intermediate VIII, reacting the intermediate VIII with n-butylamine to obtain an intermediate IX, carrying out fluorination reaction and hydrolysis reaction to obtain an intermediate X, and carrying out asymmetric reduction on the intermediate X to obtain a final product PT 2385.

By analyzing the above synthetic route, we found that it has the following significant drawbacks: the route is long, the final product can be obtained after 14 steps of reaction, and the total yield is less than 9%; in the route, when the intermediate C is synthesized, the reaction temperature is 180 ℃, when the intermediate E is synthesized, the reaction temperature is 220 ℃, and the temperatures of the two steps of reactions are both high, which is not beneficial to amplification reaction; in the process of synthesizing the intermediate F by the intermediate C through two-step reaction, the atom economy is low. In view of the defects of the above routes, the invention of a process route which is short, high in total yield, relatively mild in conditions, high in atom economy and easy to realize industrial production is an urgent problem to be solved.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a novel method for preparing a HIF-2 alpha inhibitor PT 2385.

The purpose of the invention is realized by the following technical scheme:

according to the Scheme shown in Scheme1, 7 reactions were required for synthesizing intermediate H, which is a major cause of the overall process route being lengthy and poor in atom economy. Based on the method, a synthesis route is redesigned, cheap and easily-obtained p-difluorobenzene is used as a raw material and is subjected to Friedel-crafts reaction with 3-chloropropionyl chloride, and then the intermediate H can be obtained through 3 steps of substitution and oxidation reaction, so that the synthesis steps are effectively reduced, and the yield is remarkably improved. During the synthesis of intermediate VIII from intermediate H, the ketocarbonyl group was protected with 1, 2-bis (trimethylsiloxy) ethane in Scheme1, and the yield of this step was only 64%. In order to solve the problem, the yield of the reaction is obviously improved by reducing the ketonic carbonyl (the yield is 99.5%) and carrying out subsequent reaction. The process route of the PT2385 disclosed by the invention is shown in Scheme 2:

the method comprises the following operation steps:

s1 Synthesis of intermediate II

Adding a compound I, 3-chloropropionyl chloride and anhydrous aluminum trichloride into a reaction bottle, then stirring and reacting at a certain temperature, after the reaction is finished, adding water and ethyl acetate into the reaction bottle, performing liquid separation and extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing a solvent under reduced pressure to obtain an intermediate II;

the molar ratio of the compound I, 3-chloropropionyl chloride to the anhydrous aluminum trichloride is 1.0:1.0: 2.0-1.0: 1.0:5.0, and the reaction temperature is 100-150 ℃;

s2: synthesis of intermediate III

Dissolving the intermediate II in an organic solvent, dropwise adding a sodium methyl mercaptide aqueous solution with the mass fraction of 20%, reacting at 25 ℃, detecting by TLC until the compound II disappears, adding water and ethyl acetate into the reaction liquid, separating and extracting, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and removing the solvent under reduced pressure to obtain an intermediate III;

the molar ratio of the intermediate II to the sodium methyl mercaptide is 1.0: 1.0-1.0: 3.0, the organic solvent is one or more of acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide and N-methylpyrrolidone, and N, N-dimethylformamide is preferred;

s3: synthesis of intermediate IV

Dissolving the intermediate III in dichloromethane, adding 85% m-chloroperoxybenzoic acid by mass fraction at 0 ℃, then stirring and reacting at 25 ℃, detecting by TLC until the compound III disappears, adding water into the reaction liquid, separating and extracting, drying the organic layer by using anhydrous sodium sulfate, carrying out suction filtration, decompressing and removing the solvent, and recrystallizing by using a mixed solvent of petroleum ether and ethyl acetate (4:1, v: v) to obtain an intermediate IV;

the molar ratio of the intermediate III to m-chloroperoxybenzoic acid is 1.0: 2.0-1.0: 5.0;

s4: synthesis of intermediate V

Dissolving the intermediate IV in methanol, adding sodium borohydride at 0 ℃, then stirring at 25 ℃ for reaction, detecting by TLC until the intermediate IV disappears, removing the solvent under reduced pressure, adding dichloromethane and water, performing liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain an intermediate V;

the molar ratio of the intermediate IV to the sodium borohydride is 1.0: 1.0-1.0: 3.0;

s5: synthesis of intermediate VI

Dissolving the intermediate V and 3-hydroxy-5-bromoxynil in N-methylpyrrolidone, adding a proper alkali, then reacting at 120 ℃, detecting by TLC until the intermediate V disappears, adding water into the reaction liquid, continuing stirring, carrying out suction filtration, and washing the filter cake with water to obtain an intermediate VI;

the alkali is one or more of sodium carbonate, potassium carbonate, cesium carbonate or potassium phosphate, preferably cesium carbonate, and the molar ratio of the intermediate V, 3-hydroxy-5-bromoxynil and the alkali is 1.0:1.0: 1.0-1.0: 3.0: 4.0;

s6: synthesis of intermediate VII

Adding the intermediate VI, zinc cyanide and N, N-dimethylformamide into a reaction bottle, adding a1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane compound under the protection of nitrogen, reacting at 110 ℃, detecting by TLC until the intermediate VI disappears, adding water into the reaction solution, continuing stirring, carrying out suction filtration, and washing the filter cake with water to obtain an intermediate VII;

the molar ratio of the intermediate VI to the zinc cyanide to the 1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride (II) dichloromethane compound is 1.0:1.0: 0.01-1.0: 2.0: 0.05;

s7: synthesis of intermediate VIII

Dissolving the intermediate VII in dichloromethane, adding Dess-Martin oxidant in an ice bath, reacting at 25 ℃, detecting by TLC until the intermediate VII disappears, performing suction filtration, washing the filtrate with saturated sodium bicarbonate water solution and water in sequence, drying the organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain an intermediate VIII;

the molar ratio of the intermediate VII to the Dess-Martin oxidant is 1.0: 1.0-1.0: 5.0;

s8: synthesis of intermediate IX

Sequentially adding the intermediate VIII, cyclohexane, n-butylamine and trifluoroacetic acid into a reaction bottle, then reacting at 80 ℃, detecting by TLC until the intermediate VIII disappears, distilling off the cyclohexane under reduced pressure, adding ethyl acetate and water, separating liquid for extraction, washing an organic layer by using a saturated sodium bicarbonate aqueous solution and a saturated salt solution in sequence, drying the organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and removing a solvent under reduced pressure to obtain an intermediate IX;

the molar ratio of the intermediate VIII to the n-butylamine to the trifluoroacetic acid is 1.0:1.0: 0.1-1.0: 2.0: 0.3;

s9: synthesis of intermediate X

Adding the intermediate IX, anhydrous sodium sulfate and acetonitrile into a reaction bottle, then adding 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor), carrying out reflux reaction, detecting by TLC until the intermediate IX disappears, returning the temperature to room temperature, adding concentrated hydrochloric acid, continuing stirring for reaction for 0.5h, adding ethyl acetate and water, carrying out liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and removing the solvent under reduced pressure to obtain an intermediate X;

the molar ratio of the intermediate IX, anhydrous sodium sulfate, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt and concentrated hydrochloric acid is 1.0:2.0:2.0: 10.0-1.0: 6.0:6.0: 20.0;

s10: synthesis of PT2385

Adding the intermediate X, triethylamine and formic acid into a reaction bottle, adding N- [ (1R,2R) -1, 2-diphenyl-2- (2- (4-methylbenzyloxy) ethylamino) ethyl ] -4-methylbenzenesulfonamide (chloro) ruthenium (II) under the protection of nitrogen, reacting at room temperature, detecting by TLC until the intermediate X disappears, adding ethyl acetate and water, performing liquid separation and extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, removing the solvent under reduced pressure to obtain a crude PT2385 product, and recrystallizing by using ethyl acetate to obtain a fine product;

the molar ratio of the intermediate X, triethylamine, formic acid and N- [ (1R,2R) -1, 2-diphenyl-2- (2- (4-methylbenzyloxy) ethylamino) ethyl ] -4-methylbenzenesulfonamide (chloro) ruthenium (II) is 1.0:2.0:3.0: 0.001-1.0: 4.0:10: 0.005.

Compared with the prior art, the invention has the beneficial effects that:

(1) the synthesis route provided by the invention is more reasonable, the reaction steps are simple, 14 steps of reaction are required for the reported synthesis route, the total yield is less than 9%, the process route provided by the invention is 10 steps of reaction, the total yield is up to 47.6%, and the ee value of the product is more than 99%;

(2) by changing reaction raw materials and routes, the yield is improved, and the atom economy of the reaction is effectively improved;

(3) the method avoids multi-step high-temperature reaction, has relatively mild reaction conditions, and is suitable for industrial production.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the following embodiments further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically at the end of the reaction when starting material is lost.

Example 1:

embodiment 1 of the present invention provides a preparation method of an intermediate II, and the synthetic route thereof is as follows:

the preparation method specifically comprises the following steps:

compound I (50.0g, 0.44mol), 3-chloropropionyl chloride (55.6g, 0.44mmol) and aluminium trichloride anhydrous (116.9g, 0.88mmol) were added to a reaction flask and the reaction was stirred at 120 ℃ for 12 h. The temperature was returned to room temperature, water (500mL) and ethyl acetate (500mL) were added to the reaction flask, liquid-separation extraction was performed, the organic layer was dried over anhydrous sodium sulfate, suction filtration was performed, and the solvent was removed under reduced pressure to obtain 69.8g of a pale yellow solid with a yield of 94.7%.

The identification of intermediate II prepared in this example gave the following results:

ESI-MS(m/z):169.1；

¹H NMR(300MHz,CDCl₃)δ7.32–7.19(m,1H),7.03–6.96(m,1H),3.22–3.11(m,2H),2.83–2.72(m,2H)。

example 2:

embodiment 2 of the present invention provides a preparation method of an intermediate III, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

intermediate II (55.0g, 0.33mol) was dissolved in N, N-dimethylformamide (200mL), followed by dropwise addition of a 20% by mass aqueous solution of sodium thiomethoxide (126.1g, 0.36mol), reaction at room temperature for 8 hours, addition of water (200mL) and ethyl acetate (300mL) to the reaction solution, extraction by liquid separation, drying of the organic layer over anhydrous sodium sulfate, suction filtration, removal of the solvent under reduced pressure to give 60.3g of a tan solid in 93.9% yield.

The identification of intermediate III prepared in this example gave the following results:

ESI-MS(m/z):197.2；

¹H NMR(300MHz,CDCl₃)δ7.24(t,J＝8.4Hz,1H),7.07(dd,J＝8.5,4.0Hz,1H),3.19–3.12(m,2H),2.78–2.71(m,2H),2.51(s,3H)。

example 3:

embodiment 3 of the present invention provides a preparation method of an intermediate IV, and the synthetic route thereof is as follows:

intermediate III (60.0g, 0.31mol) was dissolved in dichloromethane (300mL), and 85% by mass of m-chloroperoxybenzoic acid was added at 0 ℃ followed by stirring at 25 ℃ for 18 hours, water was added to the reaction solution, extraction was carried out, the organic layer was dried over anhydrous sodium sulfate, suction filtration was carried out, the solvent was removed under reduced pressure, and recrystallization was carried out using a mixed solvent of petroleum ether and ethyl acetate (4:1, v: v) to give 61.2g of a white solid with a yield of 87.7%.

The identification of intermediate IV prepared in this example gave the following results:

ESI-MS(m/z):229.2；

¹H NMR(400MHz,DMSO-d₆)δ8.10–7.96(m,1H),7.75(t,J＝8.4Hz,1H),3.41(s,3H),3.22–3.12(m,2H),2.88–2.76(m,2H)。

example 4:

embodiment 4 of the present invention provides a preparation method of an intermediate V, and the synthetic route thereof is as follows:

the preparation method specifically comprises the following steps:

intermediate IV (55.0g, 0.24mol) was dissolved in methanol (350mL), sodium borohydride (9.1g, 0.24mol) was added at 0 deg.C, followed by stirring at 25 deg.C for 2h, the solvent was removed under reduced pressure, methylene chloride and water were added, liquid-separation extraction was performed, the organic layer was dried over anhydrous sodium sulfate, suction filtration was performed, and the solvent was removed under reduced pressure to give 55.2g of a pale yellow solid with a yield of 99.5%.

The compound V prepared in this example was identified as follows:

ESI-MS(m/z):231.2；

¹H NMR(300MHz,CDCl₃)δ7.84(ddt,J＝8.6,4.6,0.8Hz,1H),7.16(t,J＝8.3Hz,1H),5.68(dtd,J＝7.0,3.5,1.4Hz,1H),3.70–3.56(m,1H),3.20(s,3H),3.24–3.16(m,1H),3.04–2.83(m,1H),2.50(ddt,J＝13.8,8.8,6.9Hz,1H),2.26(dddd,J＝13.8,8.4,4.6,3.7Hz,1H)。

example 5:

embodiment 5 of the present invention provides a preparation method of intermediate VI, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

compound V (40g, 0.17mol) and 3-hydroxy-5-bromoxynil (36.5g, 0.19mol) were dissolved in N-methylpyrrolidone (300mL), cesium carbonate (62.3g, 0.19mol) was added, followed by reaction at 120 ℃ for 12h, water was added to the reaction solution, stirring was continued, suction filtration was performed, the filter cake was washed with water, and drying was carried out to give 63.8g of an off-white solid in 91.5% yield.

The compound VI obtained in this example was identified as follows:

ESI-MS(m/z):402.2；

¹H NMR(300MHz,DMSO-d₆)δ7.83–7.71(m,1H),7.54–7.31(m,1H),7.23–7.20(m,1H),7.17–6.97(m,2H),5.64(d,J＝6.0Hz,1H),5.55(d,J＝6.4Hz,1H),3.35(s,3H),3.07–2.96(dt,J＝13.1,8.0Hz,1H),2.89–2.72(m,1H),2.44–2.25(m,1H),2.20–1.96(m,1H)。

example 6:

example 6 of the present invention provides a preparation method of an intermediate VII, which comprises the following synthetic route:

adding the intermediate VI (60.0g, 0.15mol), zinc cyanide (17.6g, 0.15mol) and N, N-dimethylformamide (320mL) into a reaction bottle, adding 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex (1.2g,1.5mmol) under the protection of nitrogen, then reacting for 16h at 110 ℃, adding water into the reaction liquid, continuing stirring, performing suction filtration, and washing a filter cake with water to obtain 49.3g of light yellow solid with the yield of 94.9%.

Compound VII, prepared in this example, was identified as follows:

ESI-MS(m/z):348.4；

¹H NMR(300MHz,DMSO-d₆)δ7.82–7.66(m,2H),7.54–7.41(m,2H),7.11(d,J＝8.5Hz,1H),5.63(td,J＝6.5,1.8Hz,1H),5.52(d,J＝6.5Hz,1H),3.33(s,3H),2.99(dt,J＝16.2,8.0Hz,1H),2.76(ddd,J＝16.5,8.9,2.7Hz,1H),2.31(dtd,J＝13.6,8.7,6.7Hz,1H),2.02(ddt,J＝13.3,7.9,2.3Hz,1H).

example 7:

embodiment 7 of the present invention provides a preparation method of an intermediate VIII, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

intermediate VII (45.0g, 0.13mol) was dissolved in dichloromethane (600mL), Dess-Martin oxidant (54.9g, 0.13mol) was added in an ice bath, followed by reaction at room temperature for 4h, suction filtration was performed, the filtrate was washed with saturated aqueous sodium bicarbonate solution and water in this order, the organic layer was dried over anhydrous sodium sulfate, suction filtration was performed, and the solvent was removed under reduced pressure to give 43.8g of a pale yellow solid with a yield of 97.9%.

The identification of intermediate VIII prepared in this example gave the following results:

ESI-MS(m/z):346.3；

¹H NMR(300MHz,Chloroform-d)δ8.17(d,J＝8.4Hz,1H),7.32–7.28(m,1H),7.24–7.17(m,2H),7.09(dt,J＝9.0,2.3Hz,1H),3.48(s,3H),3.27–3.08(m,2H),2.97–2.78(m,2H)。

example 8:

example 8 of the present invention provides a preparation method of intermediate IX, which comprises the following synthetic route:

after intermediate VIII (35.0g, 0.10mol), cyclohexane (160mL), n-butylamine (7.4g, 0.10mol) and trifluoroacetic acid (1.16g, 0.01mol) were sequentially added to a reaction flask, followed by reaction at 80 ℃ for 10 hours, cyclohexane was distilled off under reduced pressure, ethyl acetate (200mL) and water (150mL) were added, followed by liquid-separation extraction, the organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in this order, the organic layer was dried over anhydrous sodium sulfate, filtered by suction, and the solvent was removed under reduced pressure to give 39.8g of a tan solid with a yield of 98.1%.

The identification of intermediate VIII prepared in this example gave the following results:

ESI-MS(m/z):401.5。

example 9:

embodiment 9 of the present invention provides a preparation method of an intermediate X, which comprises the following synthetic route:

intermediate IX (30.0g, 74.9mmol), anhydrous sodium sulfate (21.3g, 0.15mol) and acetonitrile (260mL) were added to a reaction flask, followed by the addition of 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (53.1g, 0.15mol), reflux reaction for 6h, returning the temperature to room temperature, addition of concentrated hydrochloric acid (27.3g, 0.75mol), continued stirring reaction for 0.5h, addition of ethyl acetate (300mL) and water (300mL), extractive solution extraction, drying of the organic layer with anhydrous sodium sulfate, suction filtration, removal of the solvent under reduced pressure, recrystallization with a mixed solvent of petroleum ether ethyl acetate (3:1, v: v) to give 24.7g of a white solid in 86.5% yield.

The identification of intermediate X prepared in this example gave the following results:

ESI-MS(m/z):382.3；

¹H NMR(300MHz,CDCl₃)δ8.21(dd,J＝8.5,0.8Hz,1H),7.36(ddd,J＝7.5,2.3,1.3Hz,1H),7.29(d,J＝1.8Hz,1H),7.26(q,J＝1.2Hz,1H),7.16(dt,J＝8.7,2.3Hz,1H),3.72–3.57(m,2H),3.43(d,J＝4.8Hz,3H).

example 10:

the embodiment 10 of the invention provides a preparation method of PT2385, and the synthetic route is as follows:

adding the intermediate X (25.0g, 72.4mmol), triethylamine (14.7g, 0.14mol) and formic acid (10.0g, 0.22mol) into a reaction bottle, adding N- [ (1R,2R) -1, 2-diphenyl-2- (2- (4-methylbenzyloxy) ethylamino) ethyl ] -4-methylbenzenesulfonamide (chloro) ruthenium (II) (47.1mg, 0.07mmol) under the protection of nitrogen, reacting at room temperature for 12h, adding ethyl acetate and water, carrying out liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, removing the solvent under reduced pressure to obtain a crude PT2385 product, and recrystallizing by using ethyl acetate to obtain a white pure product 23.6g, wherein the yield is 85.0%, and the ee is more than 99%.

The PT2385 obtained in this example was identified to obtain the following results:

ESI-MS(m/z):384.3；

¹H NMR(300MHz,DMSO-d₆)δ7.89–7.74(m,2H),7.72–7.53(m,2H),7.17(d,J＝8.7Hz,1H),6.87(d,J＝6.9Hz,1H),5.41(dd,J＝13.1,6.8Hz,1H),3.68–3.39(m,2H),3.33(s,3H).

the above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.